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An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities
Transcriptional Mediator controls diverse gene programs for various developmental and pathological processes. The human Mediator MED23/R617Q mutation was reported in a familial intellectual disability (ID) disorder, although the underlying mechanisms remain poorly understood. Constructed by gene edi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018335/ https://www.ncbi.nlm.nih.gov/pubmed/36718943 http://dx.doi.org/10.1093/nar/gkad025 |
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author | Yang, Yenan Li, Chonghui Chen, Ziyin Zhang, Yiyang Tian, Qing Sun, Meiling Zhang, Shuai Yu, Miao Wang, Gang |
author_facet | Yang, Yenan Li, Chonghui Chen, Ziyin Zhang, Yiyang Tian, Qing Sun, Meiling Zhang, Shuai Yu, Miao Wang, Gang |
author_sort | Yang, Yenan |
collection | PubMed |
description | Transcriptional Mediator controls diverse gene programs for various developmental and pathological processes. The human Mediator MED23/R617Q mutation was reported in a familial intellectual disability (ID) disorder, although the underlying mechanisms remain poorly understood. Constructed by gene editing, the Med23/R617Q knock-in mutant mice exhibited embryonic lethality due to the largely reduced Med23/R617Q protein level, but the R617Q mutation in HEK293T cells didn’t change its expression and incorporation into Mediator Complex. RNA-seq revealed that MED23/R617Q mutation disturbed gene expression, related to neural development, learning and memory. Specifically, R617Q mutation reduced the MED23-dependent activities of ELK1 and E1A, but in contrast, upregulated the MAPK/ELK1-driven early immediate genes (IEGs) JUN and FOS. ChIP-seq and Hi-C revealed that the MED23 R617Q mutation reprogramed a subset of enhancers and local chromatin interactions, which correlated well with the corresponding gene expression. Importantly, the enhancers and chromatin interactions surrounding IEGs were unchanged by the R617Q mutation, but DACH1, an upstream repressor of IEGs, showed reduced enhancer-promoter interactions and decreased expression in mutant cells, thus relieving its inhibition to the intellectual-related IEGs. Overall, unraveling the MED23-DACH1-IEG axis provides a mechanistic explanation for the effects of the MED23/R617Q mutation on gene dysregulation and inherited ID. |
format | Online Article Text |
id | pubmed-10018335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-100183352023-03-17 An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities Yang, Yenan Li, Chonghui Chen, Ziyin Zhang, Yiyang Tian, Qing Sun, Meiling Zhang, Shuai Yu, Miao Wang, Gang Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Transcriptional Mediator controls diverse gene programs for various developmental and pathological processes. The human Mediator MED23/R617Q mutation was reported in a familial intellectual disability (ID) disorder, although the underlying mechanisms remain poorly understood. Constructed by gene editing, the Med23/R617Q knock-in mutant mice exhibited embryonic lethality due to the largely reduced Med23/R617Q protein level, but the R617Q mutation in HEK293T cells didn’t change its expression and incorporation into Mediator Complex. RNA-seq revealed that MED23/R617Q mutation disturbed gene expression, related to neural development, learning and memory. Specifically, R617Q mutation reduced the MED23-dependent activities of ELK1 and E1A, but in contrast, upregulated the MAPK/ELK1-driven early immediate genes (IEGs) JUN and FOS. ChIP-seq and Hi-C revealed that the MED23 R617Q mutation reprogramed a subset of enhancers and local chromatin interactions, which correlated well with the corresponding gene expression. Importantly, the enhancers and chromatin interactions surrounding IEGs were unchanged by the R617Q mutation, but DACH1, an upstream repressor of IEGs, showed reduced enhancer-promoter interactions and decreased expression in mutant cells, thus relieving its inhibition to the intellectual-related IEGs. Overall, unraveling the MED23-DACH1-IEG axis provides a mechanistic explanation for the effects of the MED23/R617Q mutation on gene dysregulation and inherited ID. Oxford University Press 2023-01-31 /pmc/articles/PMC10018335/ /pubmed/36718943 http://dx.doi.org/10.1093/nar/gkad025 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Gene regulation, Chromatin and Epigenetics Yang, Yenan Li, Chonghui Chen, Ziyin Zhang, Yiyang Tian, Qing Sun, Meiling Zhang, Shuai Yu, Miao Wang, Gang An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
title | An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
title_full | An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
title_fullStr | An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
title_full_unstemmed | An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
title_short | An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
title_sort | intellectual disability-related med23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018335/ https://www.ncbi.nlm.nih.gov/pubmed/36718943 http://dx.doi.org/10.1093/nar/gkad025 |
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